Abstract
Objective: To assess the differences between patients with hepatic insufficiency and healthy subjects with regard to the pharmacokinetics, cardiac safety and overall safety of ebastine and its active metabolite carebastine.
Design: Open-label parallel-group study.
Participants: 24 patients with varying degrees of hepatic insufficiency, as categorised by the Child-Pugh classification, and 12 healthy volunteers.
Methods: Healthy subjects and patients with Child-Pugh class A (n = 8) or B (n = 8) received ebastine 20mg once daily for 7 days. Patients with Child-Pugh class C (n = 8) [single or repeated dose] received ebastine 10mg. Plasma concentrations of ebastine and carebastine were determined for 23.5 hours following the initial dose on day 1 and for 96 hours following the dose on day 7 by using a sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 µg/L for ebastine and 1.00 µg/L for carebastine. Hepatic function was assessed by blood clearance of indocyanine green 0.5 mg/kg administered intravenously on day 2. Cardiac and overall safety parameters were monitored.
Results: Overall, the pharmacokinetics of ebastine were not modified by hepatic impairment. No correlation between ebastine pharmacokinetics and hepatic function, as expressed by indocyanine green clearance, was observed. Comparison of the effective half-life of ebastine and carebastine between groups did not show relevant differences. Therefore, no apparent accumulation of ebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics both in healthy subjects and in hepatically impaired patients. Finally, no apparent difference was noted in the safety of ebastine between patients with hepatic insufficiency and healthy subjects as assessed by evaluation of adverse events, vital signs and laboratory parameters.
Conclusion: Ebastine can be safely administered to patients with impaired hepatic function, as no clinically important differences can be anticipated from the pharmacokinetics and safety profile of ebastine/carebastine as compared with healthy subjects. Nevertheless, the dosage used in severely impaired patients (10mg daily) was half that used in patients with mild to moderate impairment, and any comedication did not include drugs affecting liver function; in clinical practice, both these factors should be taken into account.
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References
Luria X. Comparative clinical studies with ebastine: efficacy and tolerability. Drug Saf 1999; 21: 63–7
Hurst M, Spencer CM. Ebastine: an update of its use in allergic disorders. Drugs 2000; 59: 981–1006
Ratner PH, Lim JC, Georges GC. Comparison of once-daily ebastine 20mg, ebastine 10mg, loratadine 10mg, and placebo in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 2000; 105: 1101–7
Estelle F, Simons R. H1-receptor antagonists: safety issues. Ann Allergy Asthma Immunol 1999; 83: 481–8
Horak F, Stubner UP. Comparative tolerability of second generation antihistamines. Drug Saf 1999; 20: 385–401
Moss AJ, Chaikin P, Garcia JD, et al. A review of the cardiac systemic side-effects of antihistamines: ebastine. Clin Exp Allergy 1999; 29 Suppl. 3: 200–5
Fujii T, Matsumoto S, Hatoyama T, et al. Studies on the first-pass metabolism of ebastine in rats. Arzneimittel Forschung 1997; 47: 949–53
Huang MY, Wilson J, Argenti D, et al. Comparative pharmacokinetics of ebastine/carebastine in liver cirrhosis and healthy volunteers following administration of a 10mg ebastine tablet [abstract]. Pharm Res 1993; 10: S390
Wagner JG. Drug accumulation. J Clin Pharmacol 1967; 7: 84–8
Abad-Lacruz A, Cabre E, Gonzalez-Huix F, et al. Routine tests of renal function, alcoholism, and nutrition improve the prognostic accuracy of Child-Pugh score in nonbleeding advanced cirrhotics. Am J Gastroenterol 1993; 88: 382–7
Vincent J, Liminana R, Meredith PA, et al. The pharmacokinetics, antihistamine and concentration-effect relationship of ebastine in healthy subjects. Br J Clin Pharmacol 1988; 26: 497–502
Yamaguchi T, Hashizume T, Matsuda M, et al. Pharmacokinetics of the H1-receptor antagonist ebastine and its active metabolite carebastine in healthy subjects. Arzneimittel Forschung 1994; 44: 59–64
Marino EL, Jansat JM, March MA, et al. Parameterization by nonlinear regression analysis of the active acid metabolite of ebastine using different weighting methods. Int J Clin Pharmacol Ther 1996; 34: 546–9
Kawasaki S, Sugiyama Y, Iga T, et al. Hepatic clearances of antipyrine, indocyanine green, and galactose in normal subjects and in patients with chronic liver diseases. Clin Pharmacol Ther 1998; 44: 217–24
Gillen M, Pentikis HS, Rhodes G, et al. Pharmacokinetic and pharmacodynamic interaction of ebastine and erythromycin [abstract]. J Clin Pharmacol 1998; 38: 878
Rohatagi S, Gillen M, Aubeneau M, et al. Effect of age and gender on the pharmacokinetics of ebastine after single and repeated dosing in healthy subjects. Int J Clin Pharmacol Ther 2001; 39: 126–34
Huang MY, Argenti D, Wilson J, et al. Pharmacokinetics and electrocardiographic effect of ebastine in young versus elderly healthy subjects. Am J Ther 1998; 5: 153–8
Bernardi M, Calandra S, Colantoni A, et al. Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors. Hepatology 1998; 27: 28–34
Acknowledgements
The research at each of the three clinical sites was supported by a grant from Rhône-Poulenc-Rorer. None of the authors have any commercial interest in the drug or data.
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Lasseter, K.C., Dilzer, S.C., Vargas, R. et al. Pharmacokinetics and Safety of Ebastine in Patients with Impaired Hepatic Function Compared with Healthy Volunteers. Clin Pharmacokinet 43, 121–129 (2004). https://doi.org/10.2165/00003088-200443020-00004
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DOI: https://doi.org/10.2165/00003088-200443020-00004